Gene therapy requires affordable, scaleable technology for the specific delivery of a gene of interest to the nuclear compartment of a target cell without triggering an immune response. Although viral and nonviral vectors have been designed to deliver DNA to cells, interest in nonviral vectors has grown from the promise that they can overcome numerous limitations inherent in manipulating viruses including their complexity, difficulty to adapt to large-scale production and ease of triggering an immune response. The nonviral approach described in this proposal, the engineering of a naturally-occurring nano scale structure, is unique and largely unprecedented. However, given the significant challenges that must be overcome before successful gene therapy can be achieved, a bold new approach is warranted. The vault particle is a highly conserved, abundant and ubiquitous nanocapsule with a large internal capacity to encapsulate and protect labile biological compounds such as nucleic acids. Although the 13 MDa mass of the particle makes it nearly four times the size of the ribosome, the particle is composed of multiple copies of just three proteins and one or more small untranslated RNAs. One of these proteins, MVP, is the major structural protein of the particle. When expressed in insect cells, 96 copies of MVP can assemble into the basic vault capsule. Molecular manipulation of the MVP cDNA allows packaging of specific peptides and proteins into the vault lumen. This proposal outlines a strategy to manipulate the vault nanocapsule so that it can be used to specifically package nucleic acids. In addition, an approach is delineated to modify the particle with cell targeting signals that will allow the specific targeting of these structures to normal or neoplastic cells.